SIRT1 Contributes in Part to Cisplatin Resistance in Cancer Cells by Altering Mitochondrial Metabolism
| Autor: | Adorjan Aszalos, Jun-Jie Yin, Ding Wu Shen, Michael M. Gottesman, Toren Finkel, Xing-Jie Liang |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Small interfering RNA Carcinoma Hepatocellular Cell Survival DNA damage Immunoblotting Fluorescent Antibody Technique Antineoplastic Agents Adenocarcinoma Deoxyglucose Mitochondrion Biology Article Oxygen Consumption Sirtuin 1 Tumor Cells Cultured medicine Humans Sirtuins Gene silencing RNA Small Interfering Molecular Biology Membrane Potential Mitochondrial Cisplatin Liver Neoplasms Electron Spin Resonance Spectroscopy Flow Cytometry Cellular Structures Mitochondria Cell biology Oncology Drug Resistance Neoplasm Cancer cell Carcinoma Squamous Cell Cancer research biology.protein Histone deacetylase medicine.drug |
| Zdroj: | Molecular Cancer Research. 6:1499-1506 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Tumors frequently develop resistance to cisplatin, a platinum drug used as a cornerstone of present-day chemotherapy regimens, significantly decreasing its usefulness in the clinic. Although it is known that cisplatin-resistant (CP-r) cancer cells commonly grow more slowly and exhibit reduced uptake of various compounds, including nutrients, the effect of tumor metabolism on cisplatin resistance is unclear. It was found that in CP-r cells, uptake of 2-deoxyglucose was reduced due to dysfunction and altered morphology of mitochondria compared with cisplatin-sensitive parental cancer cells. The CP-r cells overexpressed SIRT1, a histone deacetylase that plays a central role in DNA damage response and transcriptional silencing. Incubation of drug-sensitive cells in low glucose medium induced the expression of SIRT1 and increased cellular resistance to cisplatin. Reduced SIRT1 expression by a SIRT1 SMART small interfering RNA duplex sensitized the >20-fold resistant CP-r cells to cisplatin treatment 1.5- to 2-fold, and SIRT1 overexpression by SIRT1 cDNA transfection increased cisplatin resistance in cisplatin-sensitive cells by 2- to 3-fold. Our findings therefore suggest that reduced glucose use and altered mitochondrial metabolism mediated by SIRT1 is one of several alterations that contribute to cellular resistance to cisplatin. (Mol Cancer Res 2008;6(9):1499–506) |
| Databáze: | OpenAIRE |
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